Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis

Area of Science:

• Oncology
• Metabolic Medicine
• Cancer Biology

Background:

• Peritoneal metastasis (PM) from gastrointestinal and gynecological cancers causes nutritional deficits, including increased resting energy expenditure (REE), muscle loss, and protein catabolism.
• Cancer cachexia anorexia syndrome (CAS) is common in advanced PM, characterized by anorexia, weight loss, and inflammation, leading to mortality from metabolic dysfunction.
• The etiology of CAS in PM is complex, involving tumor growth, host inflammatory responses, cytokine release, and treatment side effects.

Purpose of the Study:

• To elucidate the metabolic reprogramming in cancer cells within the peritoneal cavity during PM.
• To understand the role of hypoxia-inducible factor-1α (HIF-1α) in driving metabolic changes and anoikis resistance in PM.
• To review the challenges in treating CAS in PM and potential therapeutic strategies.

Main Methods:

• Analysis of metabolic alterations in cancer cells associated with peritoneal metastasis.
• Investigation of the role of hypoxia-inducible factor-1α (HIF-1α) in regulating glucose and alternative substrate metabolism.
• Review of current therapeutic approaches and challenges in managing cancer cachexia anorexia syndrome (CAS) in PM patients.

Main Results:

• Metabolic reprogramming, including enhanced glycolysis via HIF-1α activation, is crucial for cancer cell survival and growth in the peritoneal cavity.
• HIF-1α upregulates key glycolytic enzymes (e.g., hexokinase II, PKM2) and glucose transporters (GLUT), while also promoting glutamine and fatty acid utilization.
• Cancer cells interact with stromal cells (fibroblasts, adipocytes) and utilize autophagy to meet metabolic demands.
• Pressurized intraperitoneal aerosol chemotherapy (PIPAC) demonstrated potential in stabilizing nutritional status in PM patients.

Conclusions:

• Metabolic changes in CAS associated with PM are primarily driven by systemic inflammation rather than starvation adaptation.
• HIF-1α-mediated metabolic reprogramming is a critical mechanism for cancer cell survival and proliferation in the peritoneal environment.
• Effective therapy for CAS in PM remains challenging, with novel agents targeting these mechanisms under development; PIPAC shows initial promise.